Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study

Circ Cardiovasc Interv. 2011 Jun;4(3):273-9. doi: 10.1161/CIRCINTERVENTIONS.110.960997. Epub 2011 Apr 26.

Abstract

Background: Safety concerns have recently emerged based on a drug interaction between clopidogrel and proton pump inhibitors leading to reduced pharmacodynamic effects. However, whether such drug interaction is a class effect or a drug effect and if this can be modulated by timing of drug administration remains a matter of debate. The aim of this study was to assess the impact of high-dose pantoprazole therapy, a proton pump inhibitor with low potential to interfere with clopidogrel metabolism, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects.

Methods and results: This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy (600-mg loading dose followed by a 75-mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y(12) system at 3 time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary end point was the comparison of P2Y(12) reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week. After 1 week, there were no significant difference in P2Y(12) reactivity index between the CONC and STAG regimens (least-squares mean±SEM, 56.0±3.9% versus 56.1±3.9%; P=0.974), as well as when compared with the clopidogrel-only regimen (61.0±3.9%; P=0.100 versus CONC and P=0.107 versus STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y(12) assays.

Conclusions: Pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01170533.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles / pharmacology*
  • Adult
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Blood Platelets / drug effects
  • Cell Adhesion Molecules
  • Clopidogrel
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C19
  • Drug Interactions
  • Humans
  • Male
  • Microfilament Proteins
  • Pantoprazole
  • Phosphoproteins
  • Platelet Aggregation Inhibitors / pharmacology*
  • Prospective Studies
  • Proton Pump Inhibitors / pharmacology*
  • Receptors, Purinergic P2Y12 / drug effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Cell Adhesion Molecules
  • Microfilament Proteins
  • P2RY12 protein, human
  • Phosphoproteins
  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Receptors, Purinergic P2Y12
  • vasodilator-stimulated phosphoprotein
  • Clopidogrel
  • Pantoprazole
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticlopidine

Associated data

  • ClinicalTrials.gov/NCT01170533